SUMMARY Type 2 diabetes mellitus (T2D or T2DM) increases the risk for Alzheimer's disease (AD), and SORCS1 is genetically linked to both T2D and AD. We have undertaken a study of the possible role(s) for SorCS1 in metabolism of the Alzheimer's amyloid- () precursor protein (APP), in order to define the molecular mechanisms underlying this coordinate genetic linkage to both diseases. Overexpression of SorCS1c-myc in cultured cells caused a reduction (p=0.002) in generation (Lane et al., 2010). Endogenous murine A40 and 42 levels were increased (A40, p=0.044; A42, p=0.007) in the brains of female Sorcs1 hypomorphic mice, possibly paralleling the sexual dimorphism that is characteristic of the genetic associations of SORCS1 with AD and DM. Since SorL1, another AD-linked Vps10-domain protein, directly interacts with Vps35 to modulate APP metabolism, we investigated the possibility that SorCS1c-myc might interact with APP, SorL1, and/or Vps35. We readily recovered SorCS1:APP, SorCS1:SorL1, and SorCS1:Vps35 complexes from nontransgenic mouse brain. Notably, total Vps35 protein levels were decreased by 49% (p=0.009) and total SorL1 protein levels were decreased by 29% (p=0.003) in the brains of female Sorcs1-/- mice. We hypothesize that dysfunction of SorCS1 may contribute to both the APP/ disturbance underlying AD and the insulin/glucose metabolism disturbance underlying DM. In order to test this hypothesis further, we propose the following specific aims: Specific Aim 1. To evaluate the importance of SorCS1 protein interaction motifs and SorCS1/SorL1/APP complex formation on APP metabolism by: (a) Characterizing APP metabolism in cultured cells overexpressing SorCS1; (b) Testing the effects of mutations of protein-protein interacting motifs in the cytoplasmic and ectodomains of SorCS1 on both the formation of tripartite SorCS1/SorL1/APP complexes and APP metabolism; (c) Testing the effect of a putative pathogenic SorCS1 polymorphism on both the formation of tripartite SorCS1/SorL1/APP complexes and APP metabolism; (d) Confirming the importance of functional domains identified in Aim 1aii and 1aiii by viral gene transfer into primary cultures. Specific Aim 2. To employ Sorcs1 hypomorphic and plaque- forming human Swedish APP/PS bigenic mice crossed with Sorcs1 hypomorphic mice for characterization of: (i) endogenous APP metabolism; (ii) hippocampal morphometry, dendritic arborization, and spine structure; (c) learning behavior. Aging (3 mo, 6 mo, 12 mo) effects will also be studied. Specific Aim 3. To perform standard glucose and insulin tolerance tests and metabolic profile phenotyping of Sorcs1-/- mice and plaque-forming human Swedish APP/PS co-transgenic mice crossed with Sorcs1 -/- mice.